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Medication can be an effective intervention for treating the symptoms of depression. Not all antidepressants, however, work the same way. The antidepressant your doctor will prescribe you often depends on your particular symptoms of depression, potential side effects, and other factors.
Most antidepressants work by affecting chemicals in the brain known as neurotransmitters. The neurotransmitters serotonin, norepinephrine, and dopamine are associated with depression. How medications affect these neurotransmitters determines the class of antidepressants to which they belong.
Types of Antidepressants (List of Medications)
Selective serotonin reuptake inhibitors (SSRIs) – SSRIs are the most commonly prescribed type of antidepressants. They affect serotonin in the brain, and they’re likely to have fewer side effects for most people. SSRIs can include citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft).
Serotonin and norepinephrine reuptake inhibitors (SNRIs) – SNRIs are the second most commonly prescribed type of antidepressants. SNRIs can include duloxetine (Cymbalta), desvenlafaxine (Pristiq), levomilnacipran (Fetzima), and venlafaxine (Effexor).
Norepinephrine-dopamine reuptake inhibitors (NDRIs) – Bupropion (Wellbutrin) is the most commonly prescribed form of NDRI. It has fewer side effects than other antidepressants and is sometimes used to treat anxiety.
Tricyclic antidepressants – Tricyclics are known for causing more side effects than other types of antidepressants, so they are unlikely to be prescribed unless other medications are ineffective. Examples include amitriptyline (Elavil), desipramine (Norpramin), doxepin (Sinequan), imipramine (Tofranil), nortriptyline (Pamelor), and protriptyline (Vivactil).
Monoamine oxidase inhibitors (MAOIs) – MAOIs have more serious side effects, so they are rarely prescribed unless other medications do not work. MAOIs have many interaction effects with foods and other medications, so people who take them may have to change their diet and other medications. SSRIs and many other medications taken for mental illness cannot be taken with MAOIs.
Other antidepressants that don’t fit into a category are known as atypical antidepressants.
The medication prescribed is usually an antidepressant. A primary care practitioner can probably prescribe one. Factors the doctor will consider include other medical conditions, other medicines the patient is taking, side effects, and cost.
Practitioners typically start with a low dose that is gradually increased until improvement is shown. First-time antidepressants may take 4 to 6 weeks to show improvement. The doctor will monitor the side effects and measure improvement.Article continues below
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Types of Medication and Treatments
- Selective Serotonin Reuptake Inhibitors (SSRIs) SSRIs relieve symptoms by blocking the absorption (called “reuptake”) of serotonin by particular brain nerve cells. Because serotonin helps regulate mood, an SSRI helps leave more serotonin available. Most common drugs prescribed for depression, including fluoxetine (Prozac®), paroxetine (Paxil®, Pexeva®), sertraline (Zoloft®), citalopram (Celexa®), and escitalopram (Lexapro®). Side effects: insomnia (sleeplessness), sexual dysfunction, and weight gain, but fewer side effects than tricyclic antidepressants (see below).
- Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) work with a double type of action by increasing levels of serotonin and norepinephrine that inhibit these chemicals being absorbed back into brain cells. Examples: duloxetine (Cymbalta®), venlafaxine (Effexor XR®), desvenlafaxine (Pristiq®, Khedezla®), levomilnacipran (Fetzima®). Side effects: headache, nausea or upset stomach, a minor increase in blood pressure, weight gain, sexual dysfunction.
- Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs) help increase the concentrations of mood regulators in the brain. Examples: bupropion (Wellbutrin®, Aplenzin®, Forfivo XL®) and Mirtazapine (Remeron®). NDRIs may produce fewer side effects, or side effects may be different. Bupropion can cause anxiety but causes the least sexual side effects. Mirtazapine may also produce fewer sexual side effects and less nausea, but it causes weight gain and sedation.
- Tricyclic Antidepressants (TCAs) include imipramine (Tofranil®), nortriptyline (Pamelor), amitriptyline, doxepin, and desipramine (Norpramin®). Tricyclics tend to cause more side effects than newer antidepressants.TCAs work similarly to SNRIs, but they produce even more side effects. Conversely, they may ease chronic pain. Tricyclics may be prescribed when patients have tried other medications that have not worked.
- Monoamine Oxidase Inhibitors (MAOIs) include drugs such as tranylcypromine (Parnate®), phenelzine (Nardil®) and isocarboxazid (Marplan®). May be prescribed when other medications haven’t worked but can have serious side effects. MAOIs usually require a strict diet because of dangerous (or even deadly) interactions with foods (cheese, pickles, wine). MAOIs may also produce a bad reaction when taken with medications such as decongestants, birth control pills, and some herbal supplements. MAOIs can never be combined with SSRIs.
- Atypical Antidepressants. These medications do not belong to any of the common categories of antidepressants. These include trazodone, vortioxetine (Trintellix®), and vilazodone (Viibryd®). Sometimes they have novel mechanisms of action that are under development, and sometimes they act more rapidly than typical antidepressants.
- Atypical Antipsychotics (Second-Generation Antipsychotics, or SGAs). These drugs are also called second-generation antipsychotics (SGAs) and may be used for treatment-resistant depression (TRD) or very severe depressive disorder. These include aripiprazole (Abilify®), quetiapine (Seroquel® and Seroquel XR®), and olanzapine (Zyprexa®) — often used in combination with other medications including fluoxetine. Brexpiprazole (Rexulti®): is used to treat certain mental/mood disorders such as schizophrenia and depression and may also help to improve mood, sleep, appetite, and energy level.
- Newly-Approved Antidepressants Selegiline (Emsam®), an MAOI that is put on your skin as a patch, may cause fewer side effects than other MAOIs. Another newly-approved antidepressant on the market is a ketamine nasal spray called Spravato.
Other Medicinal Options
- Lithium has long been used as a mood stabilizer; it is indicated for the treatment of bipolar disorder. Lithium reduces the risk of suicide in patients with bipolar or depression by more than 60%. Lithium is used to treat and prevent episodes of mania in people with bipolar disorder, also called manic-depressive disorder. It is called an “antimanic agent.”
- Thyroid treatments: Thyroid hormone can be used in two different ways to treat unipolar major depression. Most often, thyroid hormone is used as augmentation for patients who respond insufficiently to antidepressant monotherapy and can also be started simultaneously with a tricyclic at the beginning of pharmacotherapy to accelerate response compared with tricyclic antidepressant monotherapy.
- MDMA (aka “molly” or “ecstasy”) a psychoactive substance originally used for people with PTSD
- Medical cannabis (marijuana): although clinical research in humans is not available, THC and CBD have been shown in animal models to be beneficial.
- Psychedelics such as LSD and psilocybin (the psychoactive ingredient in mushrooms) are under study. Participants are closely monitored.
Brain Stimulation Therapies
- Electroconvulsive Therapy (ECT): For treatment-resistant depression and severe depression, ECT involves transmitting short electrical impulses into the brain.
- Repetitive Transcranial Magnetic Stimulation (rTMS) is brain stimulation similar to ECT, but it uses a magnet instead of electrical current.
- Vagus Nerve Stimulation (VNS) is a treatment for major depressive disorder and treatment-resistant depression.
- Deep Brain Stimulation (DBS), first approved for Parkinson’s, provides pulses of electricity from an implanted battery pack. It is approved to treat OCD but its use in depression remains experimental.
Treating Depression with Therapy
There are 3 common types of therapy available that have good track records for treating depression:
- Cognitive Behavioral Therapy (CBT) helps assess and change negative thinking patterns associated with depression. The patient can learn coping strategies by recognizing negative thoughts. This is a structured therapy that is often limited to a certain number of visits, possibly 8-16 sessions.
- Psychodynamic Therapy encourages the patient to look at negative behaviors and try to recognize and then change them. Its theory is that bad patterns and feelings are rooted in past experiences, which the therapist works with the patient and tries to tap the unconscious processes that have led to problems and then to help change them.
- Interpersonal Therapy (IPT) looks at personal relationships and encourages the patient to make changes in life. The focus is to learn from the therapist how to improve problems and how to evaluate interactions to improve how they relate to others.
Treating Depression with Changes in Lifestyle
Changes in lifestyle and ridding yourself of old, unhealthy habits may be the most challenging part of treating your own depression. Here are some ways to improve your outlook:
- Find a meaningful purpose in your life. Having a strong sense of purpose offers a buffer against inevitable setbacks and obstacles. Activities that connect you with something greater—pursuing a college degree or mastering a challenging task —can not only provide a goal to work toward but a healthy and meaningful distraction.
- Cultivate social support. Personal connections with others (friends, family members, neighbors, etc.) provide many people with a reason to get up in the morning. Strong relationships help reduce isolation and loneliness. Join a class, make phone calls to people you’ve lost touch with, volunteer in a food kitchen or animal shelter, adopt a pet, and maintain contact with family and friends.
- Develop coping skills to help reduce stress. Identifying what causes stress and avoiding those situations can help. Learning relaxation techniques in unavoidably-difficult settings (for example, family gatherings) will make a person less subject to depression
- Get a sufficient amount of restorative sleep. The importance of quality, restorative sleep cannot be overstated. It helps maintain the brain’s function. Without adequate sleep, people are more likely to have negative thoughts and anxiety, leading to depression.
- Make sure you move, every day. Regular engagement in physical activity—even a small amount—can make a big impact. Exercise not only boosts self-confidence but improves social connections, and increases self-esteem.
- Eat clean. A diet that includes plenty of fresh whole foods, staying hydrated by consuming water throughout the day, cutting out sugary beverages and heavily-processed food, reducing caffeine and alcohol consumption can go a long way toward improving your mood.
- Stay motivated to make difficult lifestyle changes by rewarding yourself occasionally with things you enjoy. Negative attitudes deplete chemicals in the brain that create contentment. Negativity also damages the immune system and upsets the body’s hormonal balance.
A recently tested herb, Radix Polygalae, that acts on glutamate has shown a very fast onset of action of antidepressant effects in mice models; 30 minutes after extract infusion the antidepressant-like behavior changed in mice. Radix Polygalae (the root of Polygala tenuifolia) is a herb widely used in traditional Asian medicine that is thought to exert a variety of neuropsychiatric effects. Radix Polygalae extract can protect against N-methyl D-aspartate (NMDA) neurotoxicity and induce brain-derived neurotrophic factor (BDNF) expression, suggesting modulatory roles at glutamatergic synapses and possible antidepressant action. Also similarly to ketamine, Radix Polygalae appeared to acutely decrease phosphorylation of GluR1 serine-845 in the hippocampus while leaving the phosphorylation of hippocampal mTOR serine 2448 unchanged. These findings serve as preclinical evidence that Radix Polygalae extract exerts rapid-onset antidepressant effects by modulating glutamatergic synapses in critical brain circuits of depression and may be worthy of further evaluation as a safe substitute to other rapid-onset antidepressants known to have unacceptable side effects
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Studies with scopolamine IV infusion have shown antidepressant efficacy. In a double-blind, placebo-controlled, crossover clinical trial, scopolamine has been shown to be effective in MDD .
Moreover, augmentation with oral scopolamine yielded a significantly greater improvement in depression symptoms in MDD patients than placebo in a double-blind 6-week trial, with a remission rate of 65% in the active group against 20% in the placebo group .
In BD and MDD patients resistant to 2 antidepressant trials, oral scopolamine decreased depressive symptoms when compared to placebo .
As a novel antidepressant, scopolamine has been shown to produce rapid and robust antidepressant effects in currently depressed unipolar (MDD) and bipolar (BD) patients (Furey and Drevets, 2006, Drevets and Furey, 2010). Scopolamine blocks cholinergic muscarinic receptors, and previous studies have shown cholinergic-muscarinic dysregulation in mood disorders (Janowsky and Overstreet, 1990). While the rate of clinical response has been relatively high (Furey and Drevets, 2006), not all patients respond to scopolamine.
Symptoms of depression and anxiety during periods of drug abstinence can increase craving intensity and are reliable predictors of drug relapse . Indeed, higher depression and anxiety scores in drug abusers are associated with heightened reactivity to drug cues . Both human and preclinical rodent studies have highlighted a critical role of the mesolimbic dopamine (DA) system, including the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway, in cue-induced drug craving and drug seeking . Blockade of VTA muscarinic acetylcholine receptors (mAChRs) or nicotinic acetylcholine receptors (nAChRs) produces an antidepressant-like effect in the FST (Addy et al., 2015a). However, it is unknown whether VTA cholinergic mechanisms mediate behaviors associated with comorbid substance use disorders and mood or anxiety disorders during cocaine abstinence. Here, we trained rats to self-administer intravenous (i.v.) cocaine or saline for 10 days followed by a 14-day period of forced abstinence, and then examined cue-induced drug-seeking behavior or anxiety-related behavior during abstinence. First, we determined whether VTA mAChR or nAChR blockade altered cue-induced cocaine-seeking behavior. Secondly, we examined whether cocaine abstinence led to anxiogenic response in the EPM. Finally, we investigated whether VTA AChR blockade altered EPM behavioral responses in cocaine naïve and cocaine abstinent rats. Our data, revealing the ability of AChR blockade to alter cocaine-seeking and EPM behavior, is an important addition demonstrating common VTA cholinergic mechanisms that mediate both substance abuse and anxiety-related behavior. In our rat model, we also found that cocaine selfadministration and 14 days of forced abstinence produced an anxiogenic effect that was reversed by AChR blockade in the VTA. Thus, VTA mAChR or nAChR blockade, respectively, attenuated both cue-induced drug-relapse and abstinenceinduced anxiogenic responses. Taken together, these findings have important implications regarding cholinergic receptors mechanisms that could serve as possible therapeutic targets for comorbid substance use and anxiety-related disorders
A sustained antidepressant effect can be obtained with daily D-cycloserine (4-aminoisoxazolidine-3; DCS) treatment. DCS functions as a partial agonist at the NMDAR glycine site, with agonist effects predominating at low dose and antagonist effects predominating at high dose. DCS is used as a broad spectrum antibiotic for treatment of tuberculosis and has antidepressant properties in rodent models of depression (Zarate & Manji, 2008). In the 1950s, psychotropic effects of DCS were noted on symptoms such as anorexia, asthenia and insomnia in patients being treated for tuberculosis (Crane 1959, 1961). Following the discovery of DCS NMDAR-based activity and in view of theories linking NMDAR to schizophrenia, DCS has been assessed in treatment-resistant schizophrenia. At low doses, DCS produced beneficial effects in some studies; at higher doses (>250 mg/d) it was found to exacerbate psychosis (Tuominen et al. 2006). DCS has also been assessed in the treatment of anxiety disorders and for enhancement of learning and memory at doses of 50–500 mg/d with the primary goal of enhancing NMDAR function (Norberg et al. 2008). We have previously reported an exploratory trial involving the addition of 250 mg/d DCS to the ongoing pharmacotherapy of treatment-resistant MDD patients. This DCS regimen resulted in symptoms reduction; however, it did not induce significant therapeutic effects vs. placebo (Heresco-Levy et al. 2006). We hypothesized that higher DCS dosages may be necessary in order to elicit antidepressant effects, although such dosages may carry the potential danger of unwanted psychotomimetic effects. Additional support for higher DCS dosages stems from the fact that DCS doses of o500 mg/d may be required to elicit a neuroendocrine response indicative of NMDAR antagonistic activity (i.e. increase in plasma levels of luteinizing hormone; van Berckel et al. 1997, 1998).
This clinical trial is the first, to the best of our knowledge, to provide proof of concept evidence that pharmacological antagonistic activity at the NMDAR-associated glycine site can induce antidepressant effects and reduce MDD severity in humans. In this study, the glycine site partial agonist DCS titrated up to 1000 mg/d produced a significant antidepressant effect, evident on both investigator-rated and self-report assessment scales, when used as add-on therapy in MDD patients refractory to treatment. After 6 wk treatment, there was a 7.8-point greater reduction in HAMD score in patients receiving DCS vs. those receiving placebo . Our findings extend naturalistic observations indicating that DCS may influence mood-related symptoms when used for tuberculosis treatment and demonstrate for the first time beneficial DCS effects for rigorously diagnosed depression patients. Since DCS acts as a mixed agonist/antagonist at the NMDAR-associated glycine site and a previous trial assessing 250 mg/d DCS treatment (Heresco-Levy et al. 2006) did not show significant effects, the present results suggest that high (i.e. >500 mg/d) DCS dosages may be necessary for inducing NMDAR-antagonistic and antidepressant effects in MDD patients.
Studies have also shown that D-cycloserine, a partial agonist of the glycine site at low doses but an antagonist at high doses produces antidepressant actions in rodents 97 and in clinical trials in depressed patients 98. D-cycloserine has also been used to augment cognitive behavioral therapy in a number of different conditions, with some limited success 99. This is based on evidence that D-cycloserine enhancement of NMDA receptor function can augment neuroplasticity required for behavioral flexibility in models of fear extinction 100. Surprisingly, a glycine site agonist, D-serine is also reported to produce antidepressant actions 101
Sarcosine, an inhibitor of the glycine transporter 1 produces rapid antidepressant responses by increasing glycine levels 102. Moreover, there is also evidence that the antidepressant actions of sarcosine in rodent models require AMPA receptor activity and mTORC1 signaling 103. It is unclear why both glycine site antagonists and agonist produce rapid antidepressant responses, but one possibility is that these agents act at different initial cellular targets. For example, it is possible that glycine site antagonists act in an indirect fashion via inhibition of NMDA receptor function on GABA interneurons, and thereby lead to an increase in glutamate transmission similar to ketamine. In contrast, glycine site agonists could act to directly enhance glutamate-NMDA receptor function on excitatory neurons.
Thirteen years ago, an article in this journal first reported that the anesthetic medication, ketamine, showed evidence of producing rapid antidepressant effects in depressed patients who had not responded to prior treatments. Ketamine works by blocking one of the targets for the neurotransmitter glutamate in the brain, the N-methyl-D-aspartate (NMDA) glutamate receptor.
Now, a new study in Biological Psychiatry reports that enhancing, instead of blocking, that same target – the NMDA glutamate receptor – also causes antidepressant-like effects.
Scientists theorize that NMDA receptor activity plays an important role in the pathophysiology of depression, and that normalizing its functioning can, potentially, restore mood to normal levels.
Prior studies have already shown that the underlying biology is quite complex, indicating that both hyperfunction and hypofunction of the NMDA receptor is somehow involved. But, most studies have focused on antagonizing, or blocking, the receptor, and until now, studies investigating NMDA enhancement have been in the early phases.
Sarcosine is one such compound that acts by enhancing NMDA function. Collaborators from China Medical University Hospital in Taiwan and the University of California in Los Angeles studied sarcosine in an animal model of depression and, separately, in a clinical trial of depressed patients.
“We found that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression,” said Dr. Hsien-Yuan Lane, the corresponding author on the article.
In the clinical portion of the study, they conducted a 6-week trial where 40 depressed patients were randomly assigned to receive sarcosine or citalopram (Celexa), an antidepressant already on the market that was used as a comparison drug. Neither the patients nor their doctors knew which one they were receiving.
Compared to citalopram, patients receiving sarcosine reported significantly improved mood scores, were more likely to experience relief of their depression symptoms, and were more likely to continue in the study. There were no major side effects in either group, but patients receiving citalopram reported more relatively minor side effects than the patients being treated with sarcosine.
“It will be important to understand how sarcosine, which enhances NMDA receptor function, produces the interesting effects reported in this study. There are ways that its effects, paradoxically, might converge with those of ketamine, a drug that blocks NMDA receptors,” commented Dr. John Krystal, Editor of Biological Psychiatry. “For example, both compounds may enhance neuroplasticity, the capacity to remodel brain networks through experience. Also, both potentially attenuate signaling through NMDA receptors, ketamine with single doses and sarcosine, with long-term administration, by evoking an adaptive down regulation of NMDA receptors.”
Better understanding the reported findings may help to advance the development of medication treatments for patients who do not respond to available treatments. This is an important goal, with estimates indicating that as many as half of all patients do not experience complete relief of their depression.
The article is “Inhibition of Glycine Transporter-I as a Novel Mechanism for the Treatment of Depression” by Chih-Chia Huang, I-Hua Wei, Chieh-Liang Huang, Kuang-Ti Chen, Mang-Hung Tsai, Priscilla Tsai, Rene Tun, Kuo-Hao Huang, Yue-Cune Chang, Hsien-Yuan Lane, and Guochuan Emil Tsai (doi: 10.1016/j.biopsych.2013.02.020). The article appears in Biological Psychiatry, Volume 74, Issue 10 (November 15, 2013), published by Elsevier.
In our clinical study, superior efficacy of sarcosine over citalopram treatment was manifested by the following: 1) the effect sizes for between-group comparisons were substantial in all of the primary outcome measures and most of secondary outcome measures, 2) sarcosine treatment not only diminished the severity of symptomatology but also improved global function, 3) as compared with citalopram-treated patients, improvement was faster in sarcosine recipients, with 40% of subjects reaching remission at the end of week 4 and 65% at week 6, and 4) subjects given sarcosine were more likely to remit and less likely to drop out.
In a preliminary study, sarcosine, which enhances the N-methyl-D-aspartate receptor, seems to have similar antidepressant actions as NMDA antagonists.
Research increasingly suggests that modifying N-methyl-D-aspartate receptor (NMDAR) signaling (e.g., with ketamine; NEJM JW Psychiatry Sep 26 2013) can improve depression rapidly. These investigators from Taiwan studied animal and human antidepressant effects of the experimental drug sarcosine, which enhances NMDAR neurotransmission by inhibiting the glycine transporter-1 and reducing uptake inhibition of glycine, a co-agonist of the NMDAR. One researcher is a developer of sarcosine.
Rats were given sarcosine, desipramine, citalopram, or vehicle. On several measures of depression-like and anxiety-like behaviors, sarcosine had antidepressant-like actions similar to desipramine and somewhat similar to citalopram, compared with vehicle.
In a double-blind, randomized, 6-week study, 40 medication-free patients with nonrefractory major depression (mean age, 36) received citalopram (20–60 mg/day) or sarcosine (500–1500 mg/day). Sarcosine was statistically superior to citalopram in reducing depression-rating scale scores, with a large effect size (0.95); improving global functioning, with a large effect size (1.19); and inducing remission, with a medium effect size (0.63). Both antidepressants were well tolerated. In attempting to explain why NMDAR antagonists and a compound that increases NMDAR activity seem to have similar antidepressant effects, the authors suggest that both substances act similarly on AMPA receptors. Alternatively, sarcosine might activate synaptic NMDARs to increase resilience, whereas ketamine may interfere with excessive activity of extrasynaptic NMDARs. These drugs might also have a common action on some intermediate signal such as mammalian target of rapamycin (mTOR; Biol Psychiatry 2013; 74:742). In any event, NMDAR enhancers may have promise in the treatment of depression.
Sarcosine is an amino acid currently researched as a biomarker for prostate cancer. But, did you know that it may also improve the symptoms of mental health disorders such as schizophrenia and depression? Keep reading to learn more about the health benefits, side effects, and dosage of sarcosine.
What Is Sarcosine?
Sarcosine (also known as N-methylglycine) is required to produce the amino acid glycine and is also a byproduct of glycine breakdown. In the body, it is produced by turning dietary choline into glycine, or by breaking down methionine to glycine .
It is also produced in the laboratory (from chloroacetic acid and methylamine) .
Sarcosine has a distinct mild, sweet flavor. An ingredient of toothpaste for decades, it prevents cavities and causes foaming .
Mechanism of Action
The role of sarcosine in different mental health disorders stems from its effect on 2 important brain receptors:
- Activating NMDAR (N-methyl-D-aspartate receptor) – Sarcosine increases the activity of NMDAR in the same way as glycine. Both glycine and glutamate are required for increasing the activity of NMDAR, which is thought to bring about the therapeutic effects of sarcosine in schizophrenia and other mental health disorders [7, 8].
- Blocking the GlyT1 (type 1 glycine) transporter – GlyT1 maintains glycine levels in the brain. Sarcosine blocks this transporter leading to glycine builds up in the brain (which then may increase the activity of NMDAR). This could improve the symptoms of mental health disorders, including schizophrenia [9, 10].
Health Benefits of Sarcosine
1) Helps Improve Schizophrenia
Schizophrenia is one of the most serious mental health disorders in the world, and still one of the most difficult to understand. The symptoms include delusions and hallucinations (positive symptoms), flattened mood, loss of speech, and disorganized speech (negative symptoms), and difficulties with attention, memory, and decision making (cognitive symptoms) [11, 12].
Multiple studies (in 20, 38, 50, 60, and 65 patients) administered sarcosine with the usual antipsychotic treatment in patients with acute or stable schizophrenia. In all studies, sarcosine greatly improved positive, negative, and cognitive symptoms of schizophrenia more than the antipsychotic drug alone [14, 15, 16, 17, 18].
In a study of 22 patients with schizophrenia, sarcosine improved symptoms and was safe .
In a study of 49 patients, sarcosine improved overall cognitive functioning when taken with benzoate, even if their symptoms did not improve .
Two case studies further outline the role of sarcosine in schizophrenia:
- In a patient with schizophrenia treated with an antipsychotic drug (quetiapine) and an antidepressant drug (citalopram), 2 g of sarcosine daily resolved their negative symptoms in 2 weeks. The patient experienced some side effects after 4 weeks, which resolved once the sarcosine dosage was reduced back to 1 g .
- Another patient with schizophrenia with negative symptoms was treated with antipsychotics and antidepressants (olanzapine and venlafaxine), plus 2 g of sarcosine for 10 weeks. Sarcosine improved the patient’s low mood, activity, and speech (negative symptoms) .
However, in another clinical trial of 20 patients, sarcosine added to clozapine failed to improve symptoms over clozapine alone .
2) May Treat Depression
Although depression and schizophrenia sometimes occur together, they are distinct illnesses. Both involve malfunctioning of neurotransmitters in the brain (NMDAR [N-methyl-D-aspartate receptor]) and GlyT1 [type 1 glycine] transporter). Unlike schizophrenia, depression is caused by overactivity of NMDAR [6, 24].
Since sarcosine activates NMDAR, it would follow that those with depression should avoid it. Instead, studies report that sarcosine acts as an antidepressant .
In a study of 40 patients with depression, citalopram alone or with sarcosine was given for 6 weeks. Sarcosine improved mood, compared to citalopram alone .
Additionally, sarcosine improved mood faster and patients were more likely to stick to their treatment .
Sarcosine even improved low mood in depressed rats .
3) May Improve OCD
Obsessive-compulsive disorder (OCD) is another mental health disorder that causes a great deal of distress, often interfering with a person’s daily life. It is characterized by repetitive unwelcome thoughts, images, and urges until the person feels compelled to act on them to reduce feelings of anxiety and uneasiness .
In a trial of 26 OCD patients, sarcosine was administered alone or as an add-on treatment for 10-weeks. Sarcosine rapidly reduced OCD symptoms, particularly in patients who had not received any therapeutic drug treatment before the study .
4) May Reduce Impulsivity in Children
Oppositional-defiant disorder (ODD) is a disorder where children or adolescents behave in a defiant and impulsive manner (particularly towards their parents and teachers), and are often angry or irritable. Symptoms of ODD often coexist with ADHD .
A 6-week study of 116 children with ADHD found that treatment with sarcosine slightly improved ODD symptoms, but not ADHD symptoms .
5) May Help Reduce Seizures
Seizures are caused by various factors, with treatments often specific to the cause .
In mice with induced seizures treated with sarcosine:
- Sarcosine was administered each time a seizure was caused. At high doses, it increased the threshold, making it more difficult for seizures to occur .
- Sarcosine was effective in reducing the incidence of seizures and death by up to 72% .
6) Sarcosine May Reduce Neuropathic Pain
Nerve (neuropathic) pain is difficult to address. Unlike pain from physical trauma (nociceptive pain), nerve pain often results from underlying damage to the nervous system. Long-standing diabetes, stroke, and herpes zoster are some of the common causes [35, 36, 37, 38].
In rats with neuropathic pain in one paw, oral sarcosine reduced pain in both the injured and uninjured paw with higher doses showing greater pain reduction. This effect was lost shortly after it was stopped. It also reduced pain when injected into the spinal cord and brain of the rats .
7) May Reduce Anxiety
In rats suffering from anxiety (mothers being separated from pups), a sarcosine derivative (ALX 5407) decreased anxious behavior. The reduction was comparable to anti-anxiety medications like diazepam and escitalopram .
Sarcosine could reduce anxiety through a novel pathway .
8) May Reduce Harm From Toluene
Toluene is a widely-used industrial solvent that is also abused as a recreational inhalant for its intoxicating effects in the brain. Exposure can affect behavior, movement, and brain function .
Mice exposed to toluene were pretreated with sarcosine, which reversed dangerously low body temperatures, memory loss, and lack of coordination in body movements. However, it did not change the intoxicating effects of toluene. These findings show that sarcosine may have a significant role in treating toluene exposure .
9) May Reduce Damage From Stroke
Cerebral ischemia occurs when there is insufficient blood flow to the brain, which then results in the death of brain tissue or stroke.
In rats, pretreatment with sarcosine increased tolerance to blood shortage and reduced cell death in a brain region (hippocampus). Hence, sarcosine protected the brain from stroke .
Limitations and Caveats
While there are several clinical trials in humans, they are limited in sample size. Due to ethical concerns, the ability to administer sarcosine without antipsychotic drugs is limited.
The other studies were done in animals.
Hence, larger human studies are needed to confirm the beneficial effects of sarcosine.
Side Effects & Precautions
Sarcosine is a promising biomarker for prostate cancer. It may help detect prostate cancer in the early stages with some some advantages over the currently used biomarker (prostate-specific antigen or PSA) [44, 45].
However, sarcosine supplements may increase prostate cancer risk. Sarcosine might also make hamless prostate cancer cells become more dangerous and invasive, according to animal studies. What’s more, men with prostate cancer have much higher sarcosine levels in their prostate tissue, other healthy tissues, and urine .
Given the possible increase in prostate cancer risk, men may want to avoid sarcosine supplements and stick to its healthy food sources unless directed otherwise by a doctor. More information about the safety of sarcosine is needed.
Natural Sources / Forms of Supplementation
Sarcosine is readily present in a variety of food products, including egg yolks, legumes, nuts, certain vegetables, turkey, ham, and other meats .
As a supplement, sarcosine is available in bulk powders, capsules, and sometimes liquid form.
Sarcosine is taken daily with doses ranging from 1 g to 4 g, with 2 g being the most common and effective dose. If side effects occur at the 2 g dose, then the dosage can be decreased to 1 g [21, 22].
Users describe sarcosine as helpful for panic attacks, delusional thoughts, and depression, especially in combination with other supplements.
Patients with schizophrenia have reported a variety of experiences ranging from good symptom control, no change, or a worsening of positive symptoms, including decreased sleep and racing thoughts.
Some people reported improvement in a matter of days, while others saw improvement in a month’s time. The improvement was usually observed in negative symptoms of schizophrenia.
It may not be the next Prozac, but sarcosine, a substance found in muscles and other body tissues, is showing potential as a possible treatment for depression.
In a brief, six-week trial on depressed patients, sarcosine even outperformed the antidepressant citalopram (Celexa).
Sarcosine is a derivative of glycine, the smallest of the amino acids. It has previously shown to help patients with obsessive-compulsive disorder (OCD).
It may be that by simply changing the level of activity of the NMDA receptor sarcosine enhances neuroplasticity, the ability to remodel nerve networks in the brain.Scientists believe sarcosine affects mood by enhancing the activity of NMDA receptors in the brain. These receptors help the brain adapt (plasticity) and are also involved in memory.
Forty patients diagnosed with major depressive disorder were randomly chosen to receive either sarcosine or citalopram for six weeks. Neither the patients nor their doctors knew which treatment they were prescribed.
Patients receiving sarcosine reported significantly improved mood scores, were more likely to experience relief of their depression symptoms, and were less likely to drop out of the study compared to those on citalopram. There were no major side effects in either group, but patients receiving sarcosine reported fewer minor problems than patients treated with citalopram.
One thing that puzzles researchers is that ketamine and synthetic drugs that mimic it are thought to ease depression by blocking the NMDA receptor, essentially de-activating it, the exact opposite of how sarcosine works.
How can activating and de-activating the same receptor both ease depression? That’s not known yet but it’s possible that NMDA receptor underactivity can cause depression in some people, while overactivity provokes it in other people.
The researchers also speculate that simply changing the level of activity of the NMDA receptor may enhance neuroplasticity, the ability to remodel nerve networks in the brain.
Sarcosine can be taken orally. And at least in this small trial, people who took it reported fewer side effects than those who took the approved depression drug, citalopram (Celexa).
It’s been nearly three decades since the last truly new drugs to treat depression were developed. And while currently available antidepressants are the most common treatment for depression, they may increase the likelihood of depression recurring.
They also do not work for everyone, suggesting that drugs such as sarcosine, which affect different pathways, may have a role to play in helping ease the burden of depression.
An article on the study of sarcosine as antidepressant appears in Biological Psychiatry.
Sarcosine supplementation can be used to alleviate symptoms of depression and schizophrenia, or improve cognition. It is absorbed more reliably by the body than D-serine, which can also treat similar conditions.
Sarcosine is being investigated for its connection to prostate cancer. It may be a biomarker for prostate cancer, which means that if sarcosine levels in the blood are higher than normal, it could be an indicator of prostate cancer. This doesn’t mean that sarcosine itself causes cancer. More research is needed to confirm this relationship.
Sarcosine’s main mechanism involves inhibiting a transporter, called GlyT1, which takes up glycine and D-serine into cells. This increases the levels of glycine and D-serine in the body and increases their effects.
It is unknown at this time if sarcosine supplementation is harmful. It may act as a co-carcinogen, meaning it doesn’t cause cancer, but increases the effects of other cancer-causing compounds.
Sarcosine is synthesized by the glycine N-methyltransferase (GMNT) enzyme which uses a methyl group from S-Adenosyl methionine to donate to glycine, creating sarcosine and S-adenosylhomocysteine.
It can be metabolized by either the sarcosine dehydrogenase (SARDH) enzyme or pipecolic acid oxidase (PIPOX), the former of which is highly expressed in the liver but not brain and converts sarcosine into glycine.
Sarcosine is synthesized by one enzyme (which appears to modulate sarcosine concentrations in the body) and is degraded by one of two other enzymes
Due to being able to facilitate a conversion from SAMe into S-adenosylhomocysteine, sarcosine is involved in methyl donation and homeostasis and the one-carbon cycle. This pathway, and particularly the enzyme of synthesis (GMNT), appear to be fairly important as the enzyme constitutes more than 1% of all cytosolic proteins in the liver and is upregulated in response to excess methionine.
Sarcosine is involved in the one-carbon cycle alongside other methyl donating molecules, and the enzyme that creates sarcosine appears to be involved with regulating methionine concentrations in the body
NMDA receptors (a subset of glutaminergic receptors) have a glycine binding site which has become a favorable target for enhancing glutaminergic function as it carries a lower risk for excitotoxicity than other pharmaceutical interventions.
Sarcosine appears to be a co-agonist at the NMDA receptor (glycine binding site) similar to both glycine and D-serine although it has a potency of 26+/-3µM (ED50 value). Previous research failed to find such an effect, and relative to glycine (EC50 of 61+/-8nM) sarcosine appears much weaker as 300µM of sarcosine is less potent than 3µM of glycine in vitro.
When matched at the EC50 value, sarcosine appears to induce less desensitization than does glycine (did not extend to EC20 nor saturation, desensitization was 48+/-6% with sarcosine and 85+/-3% with glycine) and produces a larger calcium influx than does glycine. This calcium influx from NMDA receptors is vital to signalling through the neuron
Sarcosine is an agonist at the glycine binding site of NMDA receptors, and while it may be more potent when matched for the EC50 values it is practically weaker since it requires a much larger EC50 value to induce signalling. If the value is matched, however, then sarcosine is better at enhancing glutaminergic signalling
Sarcosine appears to be a glycine transporter 1 inhibitor (GlyT1; present on glial cells and helps regulate glycine concentrations), blocking the reuptake of glycine. This inhibition occurs somewhere in the range of 40-150µM, and although the increased amount of glycine can enhance glycinergic signalling inhibition does not appear to explain all the signalling from sarcosine.
Sarcosine can act on glycinergic receptors with an EC50 value of 3.2+/-0.7mM (3,200µM), which is significantly less potent than glycine (60μM). 100μM sarcosine failed to elicit any activation.
Appears to prevent glycine reuptake into glial cells and thus increase the exposure of glycine to the synapse, which appears to be the main mechanism. Although sarcosine can directly act on glycine receptors, it is quite weak at doing so relative to glycine .
Memory an dlearning
Activity at the glycine binding site of the NMDA receptors appears to enhance cognition secondary to enhancing NMDA signalling which can affect both youth and older rats, which is evident with synthetic agonists, mice lacking the Gly1T transporter (which sarcosine inhibits) and thus having higher glycine levels in the synapse, as well as both glycine and D-serine supplementation. Sarcosine’s inhibition of Gly1T is thought to underlie cognitive promoting effects secondary to increasing synaptic levels of glycine and D-serine, since although sarcosine can directly act as a coagonist it is significantly less potent than the other two.
Secondary to increasing synaptic levels of D-serine and glycine, sarcosine is thought to possess cognitive promoting effects in otherwise healthy and young rodents and humans
Social memory performance has been noted to be enhanced with GlyT1 transportation inhibitors (a deriviative of sarcosine in this study) and D-serine. Sarcosine is also able to attenuate the impairments of social memory, motor coordination, and novel object recognition induced by NMDA antagonists.
GlyT1 inhibitors seem to have similar cognitive enhancing properties as D-serine (as they increase synaptic D-serine concentrations), although it is fairly underresearched
NMDA signalling itself is thought to be perturbed in schizophrenic persons (and antagonists such as PCP cause or exacerbate schizophrenic symptoms) and since agonists of the glycine modulatory site such as D-serine are reduced in schizophrenic persons it is thought that the reduced NMDA function may be indirectly through reduced glycine binding site activity.
Glycine transport inhibitors (of which sarcosine is) appear to be useful in the treatment of schizophrenia secondary to increasing glycine and D-serine concentrations in the synapse, which encourages glycinergic and NMDA signalling. There are two main glycine transporters (GlyT1 and GlyT2) with 50% homology, with GlyT1 being the target of sarcosine and the more prominent one expressed on glial cells and possibly colocalized with NMDA receptors whereas GlyT2 is localized to neurons and less expressed overall and tends to be localized with the glyinergic receptors. Since GlyT1 is more apparently involved with NMDA signalling, it is thought to be more relevant to the treatment of schizophrenia.
When looking at studies using sarcosine, 2,000mg sarcosine daily for six weeks in addition to antipsychotics noted improvements in symptoms in the range of 14-16% (BPRS and PANSS rating scales) reaching up to around 20% symptom reduction relative to control.
One study in persons on clozapine failed to find a benefit with sarcosine therapy at 2,000mg which is similar to null results seen with D-serine. Since clozapine is thought to be antipsychotic via D-serine signalling this signalling pathway may already be saturated in persons on clozapine.
This magnitude of response seen with sarcosine is somewhat comparable to D-Serine at a similar dose, Glycine at a higher dose (800mg/kg), and D-cycloserine. In direct comparative studies, however, sarcosine has been twice noted to outperform D-serine which may be due to the unreliability seen with D-serine supplementation.
It should be noted that some studies by the author Guochuan Tsai have potential conflicts of interest due to the aforementioned being the creator of sarcosine (US patent 6228875) alongside Joseph Coyle. These studies include the following, although publication bias does not seem likely as the authors have published negative results previously.
Sarcosine at 2,000mg appears to be just as effective as D-serine for treating symptoms of schizophrenia when looking at the magnitude of benefit, but sarcosine seems to be more reliable and is thus currently seen as being a better therapeutic alternative
Inhibition of GlyT1 is thought to be a novel treatment for depression, and has been implicated in preliminary evidence as being more potent than the reference drug citalopram. Antidepressant effects have previously been noted with D-serine, thought to be related to enhancing glutaminergic neurotransmission.
Although it is not currently well researched, sarcosine may have anti-depressant properties secondary to enhancing glutaminergic neurotransmission .
D-Serine has been well investigated for its usage in treating cocaine dependency, and this appears to extend to both other agonsits at the glycine binding site of NMDA receptors (cycloserine) and to sarcosine as well.
May hold the same anti-addictive properties as D-serine in response to cocaine
Botanicals for depression
Herbs for Depression
1. St. John’s wort
St. John’s wort is also known as Hypericum perforatum. This plant has been a common herbal mental health treatment for hundreds of years. However, people must use caution if they chose to try it as a potential treatment for depression.
However, this review of eligible studies did not find research on the long-term effects of St. John’s wort on severe depression.
The authors also advised caution against accepting the results wholesale, as the herb has adverse effects that many of the studies did not consider.
St John’s wort can also interfere with the effects of antidepressant medication, meaning that it may make symptoms worseTrusted Source or reduce the effectiveness of conventional treatment.
While St. John’s wort might help some people, it does not show consistently beneficial effects.
For these reasons, people should not use St. John’s wort instead of conventional treatment. Neither should they try St. John’s wort to treat moderate to severe depression.
This supplement comes from the gnarled root of the American or Asian ginseng plant. Siberian, Asian, and Eleuthero ginseng are different plants with different active ingredients.
Practitioners of Chinese medicine have used ginseng for thousands of years to help people improve mental clarity and energy and reduce the effects of stress.
Some people associate these properties of ginseng with potential solutions for the low energy and motivation that can occur with depression.
However, the National Center for Complementary and Integrative Health (NCCIH) adviseTrusted Source that none of the many studies that people have conducted on ginseng have been of sufficient quality to form health recommendations.
The results show that chamomile produced more significant relief from depressive symptoms than a placebo. However, further studies are necessary to confirm the health benefits of chamomile in treating depressive symptoms.
Lavender oil is a popular essential oil. People typically use lavender oil for relaxation and reducing anxiety and mood disturbances.
A 2013 reviewTrusted Source of various studies suggested that lavender might have significant potential in reducing anxiety and improving sleep.
Lavender has mixed results in studies that assess its impact on anxiety. However, its effectiveness as a treatment for ongoing depression has little high-quality evidence in support at the current time.
Some studies cite using saffron as a safe and effective measure for controlling the symptoms of depression, such as this non-systematic review from 2018Trusted Source.
However, more research would help confirm the possible benefits of saffron for people with depression. Scientists also need to understand any possible adverse effects better.
SAMe is short for S-adenosyl methionine. It is a synthetic form of a chemical that occurs naturally in the body.
In 2016, researchers reviewed all the randomized controlled trials on record for the use of SAMe to treat depression in adults. They found no significant difference between the effects of SAMe on depression symptoms and those of a placebo.
However, they also found that SAMe had about the same effectiveness as the common antidepressants imipramine or escitalopram. Furthermore, it was better than a placebo when the researchers mixed SAMe with selective serotonin reuptake inhibitor medications.
As with many other studies into herbs and supplements, the investigations into the safety and efficacy of SAMe are of low quality. More research is necessary to determine its exact effect.
People use the supplement in Europe as a prescription antidepressant. However, the FDA have not yet approved this for use in the U.S.
7. Omega-3 fatty acids
While the study authors reported no serious side effects from the supplement, they also advised that it would only be an effective measure in treatment for depression that was due to omega-3 deficiency.
Also known as 5-hydroxytryptophan, this supplement may be useful in regulating and improving levels of serotonin in the brain. Serotonin is the neurotransmitter that affects a person’s mood.
5-HTP has undergone a number of animal studies, and some, such as this review from 2016Trusted Source, cite its potential as an antidepressant therapy. However, evidence of its effects in human subjects is limited.
5-HTP is available as an over-the-counter (OTC) supplement in the U.S. but may require a prescription in other countries.
More research is necessary, especially regarding concerns that it may cause serotonin syndrome, a serious neurological complication if a person takes 5-HTP in excess.
Supplement manufacturers do not have to prove that their product is consistent. The dose on the bottle may also be inaccurate.
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